Diversity Driven Decoration and Ligation of Fullerene by Ugi and Passerini Multicomponent Reactions

Article abstract of DOI:10.1002/chem.201802414

Aiming at providing an efficient and versatile method for the diversity-oriented decoration and ligation of fullerenes, we report the first C₆₀ derivatization strategy based on isocyanide-multicomponent reactions (I-MCRs). The approach comprises the use of Passerini and Ugi reactions for assembling pseudo-peptidic scaffolds (i.e., N-alkylated and depsipeptides, peptoids) on carboxylic acid-functionalized fullerenes. The method showed wide substrate scope for the oxo and isocyanide components, albeit the Ugi reaction proved efficient only for aromatic amines. The approach was successfully employed for the ligation of oligopeptides and polyethyleneglycol chains (PEG) to C₆₀, as well as for the construction of bis-antennary as well as PEG-tethered dimeric fullerenes. The quantum yields for the formation of ¹O₂ was remarkable for the selected compounds analyzed.

Full text of DOI:10.1002/chem.201802414

DOI: 10.1002/chem.201802414
Communication
&
Multicomponent Reactions
Diversity Driven Decoration and Ligation of Fullerene by Ugi and
Passerini Multicomponent Reactions
Bruno B. Ravanello,[a] Nalin Seixas,[a] Oscar E. D. Rodrigues,[b] Rafael S. da Silva,[b]
Marcos A. Villetti,[d] Andrej Frolov,[a] Daniel G. Rivera,[a, c] and Bernhard Westermann*[a, e]
made decoration of this molecular architecture a fascinating
Abstract: Aiming at providing an efficient and versatile
method for the diversity-oriented decoration and ligation
goal in modern synthetic chemistry.[3–5]
Recent literature reports demonstrate the unique photo-
of fullerenes, we report the first C60 derivatization strategy
physical and photochemical features of fullerenes to generate
based on isocyanide-multicomponent reactions (I-MCRs).
singlet oxygen (1O2), which can be employed in photodynamic
The approach comprises the use of Passerini and Ugi reac-
therapy (PDT). It has been demonstrated that fullerene deriva-
tions for assembling pseudo-peptidic scaffolds (i.e., N-
tives promote invalidation of cancer cells and pathogenic mi-
alkylated and depsipeptides, peptoids) on carboxylic acid-
croorganisms in vitro, besides treatment of tumors and micro-
functionalized fullerenes. The method showed wide sub-
bial infections in mouse models with almost no side effects.[6]
strate scope for the oxo and isocyanide components,
An underexplored strategy with this material is the imple-
albeit the Ugi reaction proved efficient only for aromatic
mentation of diversity-oriented methods capable to generate
amines. The approach was successfully employed for the
large sets of dissimilarly functionalized fullerenes for screening
ligation of oligopeptides and polyethyleneglycol chains
their physicochemical properties or biological activities. In an
(PEG) to C60, as well as for the construction of bis-anten-
endeavor to provide an approach enabling the rapid explora-
nary as well as PEG-tethered dimeric fullerenes. The quan-
tion of the broader exo-fullerene chemical space, we describe
1
tum yields for the formation of O2 was remarkable for the
the first implementation of isocyanide-based multicomponent
selected compounds analyzed.
reactions (I-MCRs) in fullerene chemistry.
I-MCRs are among the chemical processes with the greatest
diversity and complexity-generation capacity.[7] As a result, they
The development of novel functionalization and derivatization
methods for carbon-based materials such as fullerenes, graph-
ene and nanotubes is a crucial step in the pursuit of new prop-
erties and applications.[1,2] Functionalized fullerenes have found
remarkable applications in areas as diverse as material science,
medicinal chemistry and plant biology, which make the tailor-
have been widely employed in drug discovery, heterocycle and
natural product synthesis, and more recently in macrocycliza-
tion and polymer chemistry.[8,9] Nevertheless, the concept of
using a multicomponent approach for the diversity driven dec-
oration of fullerenes has remained elusive so far.[10] We sought
to implement this approach by using the four-component Ugi
(4CR) and three-component Passerini (3CR) reactions for the in-
stallation of pseudo-peptidic exo-fullerene moieties. Peptido-
fullerenes are of notable interests due to their biological and
medicinal relevance, and they have been previously prepared
employing standard coupling protocols.[11] Despite the efficacy
of this peptide chemistry, such couplings are not diversity-gen-
erating per se and are fixed to amino and acid components. In-
stead, the Ugi and Passerini reactions produce unique N-substi-
tuted and depsipeptide skeletons, respectively, incorporating
up to four elements of diversity, including those arising from
the oxo and the isocyanide components.
[a] B. B. Ravanello, N. Seixas, Dr. A. Frolov, Prof. Dr. D. G. Rivera,
Prof. Dr. B. Westermann
Department of Bioorganic Chemistry
Leibniz-Institute of Plant Biochemistry, Weinberg 3, 06120 Halle (Germany)
E-mail: bernhard.westermann@ipb-halle.de
[b] Prof. Dr. O. E. D. Rodrigues, R. S. da Silva
LabSelen-NanoBio—Departamento de Quꢀmica
Universidade Federal de Santa Maria
CEP 97105-900 Santa Maria, Rio Grande do Sul (Brazil)
[c] Prof. Dr. D. G. Rivera
Center for Natural Products Research
Fullereno-carboxylic acids are among the most widely used
substrates in fullerene chemistry, as they are available by a va-
riety of synthetic transformations including the Bingel–Hirsch
and Prato reactions.[12] As depicted in Scheme 1, this is another
advantage of the multicomponent diversification of fullerenes
by Ugi and Passerini reactions, as carboxy-functionalized C60,
C70 and higher ones can be used as carboxylic acid compo-
nents.
Faculty of Chemistry, University of Havana, Havana 10400 (Cuba)
[d] Prof. Dr. M. A. Villetti
Spectroscopy and Polymers Laboratory (LEPOL)
Department of Physics, Universidade Federal de Santa Maria
CEP 97105-900 Santa Maria, Rio Grande do Sul (Brazil)
[e] Prof. Dr. B. Westermann
Institute of Chemistry, Martin-Luther-University Halle-Wittenberg
Kurt-Mothes-Str. 2, 06120 Halle (Germany)
Supporting information and the ORCID identification numbers for the
authors of this article can be found under:
https://doi.org/10.1002/chem.201802414.
Variation of the aldehyde and isocyanide components is pos-
sible in both reactions, while the Ugi-4CR has greater diversity-
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amino acids) and a variety of aldehydes and isocyanides. On
the other hand, the use of aniline led to the Ugi products in
excellent yields using the solvent mixture CH2Cl2/MeOH 3:1
(v,v), which provided good substrate solubilization while it in-
cludes a polar protic solvent known to favor Ugi reactions. In
our opinion, the rationale for the superior behavior of aniline
might be found in the so-called hydrophobic effect, which
may assist the multicomponent reaction by engaging the hy-
drophobic imine (derived from aniline) and [C60]fullerenoacetic
acid 2 with the isocyanide component.[13]
Figure 1 illustrates the high structural diversity that can be
reached in functionalized [C60]-fullerenes by implementing the
Ugi reaction with carboxylic acid 2.[14] Compounds 3–5 and 7
were produced in good to excellent yields using commercially
available isocyanides, in this case proving that formaldehyde
was slightly more effective than isobutyraldehyde as oxo-com-
ponent. For addressing the scope of the amino component,
anilines bearing electron-withdrawing and donating groups
were employed, proving very poor reactivity for the former
but excellent results for the latter ones. Thus, p-methoxy-ani-
line reacted almost quantitatively to render product 6 in 96%
of isolated yield. This result paves the way for the future diver-
sification of the exo-fullerene N-aryl peptide skeleton, since
more complex p-alkyloxy-anilines are readily available building
blocks. Synthesis of the C60-amino acid-PEG chimeras 8 and 9
highlights how a bifunctional PEG-isocyanide can be used
both for improving the solubility (soluble tag) and installing a
functional handle for further functionalization.
Scheme 1. Multicomponent diversification of [C60]-fullerene 2 by Passerini
and Ugi reactions. a) p-Toluenesulfonic acid, toluene, reflux 12 h. Passerini-
3CR: CH2Cl2, 48 h, r.t. Ugi-4CR: CH2Cl2/MeOH 3:1, 48 h, r.t.
generating character as it incorporates an additional amino
component. However, herein we found that aliphatic amines
are not good substrates for the Ugi derivatization of C60, while
aromatic amines such as anilines provide excellent reaction
yields with a variety of aldehydes and isocyanides. We carried
out extensive optimization of the reaction conditions to assess
which factors might be influencing the poor reactivity of ali-
phatic amines in the Ugi reaction. For this, varied solvents and
solvent mixtures such as MeOH, CH2Cl2/MeOH, THF, DMF, and
chlorobenzene were tested, but no product formation was de-
tected with aliphatic amines (i.e., Me, iPr, Bn, and C-protected
The high level of structural complexity arising from the iso-
cyanide component is one of the strongest points of this strat-
egy. This is exemplified with the synthesis of the complex pep-
Figure 1. Chimeric [C60]-fullerenes including N-aryl peptoid, PEGs, peptides and dimer derived from the Ugi reaction. TFA: trifluoroacetic acid.
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tido-fullerenes 12 and 13 through the multicomponent ligation
of isocyano tri- and pentapeptides to carboxylic acid 2 in the
presence of aniline and formaldehyde. Indeed, such a ligation
protocol is also amenable for the incorporation of other bio-
molecular fragments of biological relevance such as lipids and
carbohydrates, as lipidic and saccharidic isocyanides are highly
available substrates nowadays.[15] An alternative for the use of
structurally complex isocyanides is the use of the convertible
one, which can easily be converted into an activated acyl
group to enable further derivatization with a good nucleo-
phile.[16] This concept has never been implemented in fullerene
chemistry, and herein it is demonstrated with the multicompo-
nent reaction of carboxylic acid 2 with the convertible isocya-
nide 4-isocyanopermethylbutane-1,1,3-triol in the presence of
aniline and formaldehyde to furnish Ugi adduct 10 in 79% of
yield. This key intermediate functionalized with a convertible
handle can be readily transformed into the acyl pyrrole deriva-
tive 11 by mild acidic treatment and be further ligated to mol-
ecules bearing for example, an amino group. A similar protocol
could be used for the ligation of fullerenes to more complex
molecular scaffolds or even for the production of multimeric or
dendritic fullerene-based architectures. Notably is the forma-
tion of the fullerene dimer 14, obtained in a single step with
the use of a bis-anilino starting material.
cyanide component. We also sought to prove that the alde-
hyde component could be an additional source of exo-fuller-
ene functional diversity. For this, carboxylic acid 2 and tert-
butyl isocyanide were reacted with aldehydes bearing a long
aliphatic chain (19), and a PEG chain (20), which demonstrated
the feasibility of using this component as a powerful diversity
element. The installation of PEG chains can be used to fulfill
the double objective of improving the solubility (soluble tag)
of C60 derivatives and introducing a reactive handle for further
functionlization. Both purposes can be accomplished by ex-
ploiting the isocyanide component, as proven in the synthesis
of compounds 18 and 21 from PEG-isocyanides and also com-
pounds 22 and 23 bearing an alternative functional handle
(methyl ester).
The use of a convertible isocyanide proved efficient once
again with the synthesis of compound 24 in excellent yield. Al-
ternatively, the ligation of isocyano peptides enabled the syn-
thesis of chimeric C60-depsipeptide 25, proving the second
case that the functionalization of fullerenes with structurally
different skeletons is possible by means of this multicompo-
nent strategy. Finally, synthesis of the fluorescently labeled ful-
lerene 26 further demonstrates the potential of this strategy
for the tailor-made exo- decoration of C60 with complex and
chemically relevant scaffolds.
After proving the great potential of the Ugi reaction for the
diversity-oriented decoration and ligation of carboxy-fullerenes,
we turned to assess the efficiency of the Passerini reaction for
the same purpose. Typically, this latter reaction proceeds
better in non-polar solvents and it usually comprises a wide
scope of the oxo-component, including complex ketones. As
depicted in Figure 2, we initially focused on assessing the sub-
strate scope with varied aldehydes and isocyanides, and later
on the installation of biologically or chemically relevant moiet-
ies. Thus, functionalized [C60]-fullerenes 15–17 were produced
in excellent yields using isobutyraldehyde and varying the iso-
An extension of the MCR-mediated diversification of ful-
lerenes is shown in Scheme 2 with the synthesis of bis-antenn-
ary [C60]-fullerenes bearing two pseudo-peptidic moieties.[17]
For this, C60-dicarboxylic acid 28 was prepared with a cis-2 con-
figuration (Nierengarten nomenclature[18]) according to a re-
ported procedure and subjected to double Ugi and Passerini
reactions to afford bis-adducts 29 and 30 in good yields. With
these simple examples, we aimed at highlighting the possibili-
ty of increasing even more the molecular complexity by incor-
porating into a bifunctional C60 up to six components in only
one step.
Figure 2. Chimeric [C60]-fullerenes including depsipeptides, PEGs and fluorescent labels derived from the Passerini reaction.
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ing through the origin, indicating a first-order kinetic for
photo-bleaching of DPBF in the presence of 3 (see insert in
Figure 3).
In this study, the rate constant of photo-oxidation of DPBF
sensitized by 3 was k=4.43ꢁ10ꢀ3 sꢀ1. The high photodynamic
activity of this compound may be mainly attributed to the
1
long lifetime of the triplet state to produce efficiently O2.[23]
Moreover, the kinetic data of DPBF photo-oxidation revealed
1
the ability of 3 to produce O2, through determination of sin-
glet oxygen quantum yield (FD). The FD of 3 was determined
by the relative method using fullerene as the reference,[24] in
accordance to Equation (1):
k
kStd
IStd
FD ¼ FSDtd
ꢁ
ꢁ
I
ð1Þ
std
in which FD is the singlet oxygen quantum yield for the
standard (1.00 for fullerene in toluene);[25] k and kstd are the
DPBF photobleaching rate constants in the presence of the re-
spective samples and standard; and I and Istd are the rates of
light absorption at the irradiation wavelength of laser by the
samples and standard, respectively. The measured value of FD
for 3 was 0.91 indicating that it is very efficient to produce sin-
glet oxygen in this medium.
Scheme 2. Synthesis of bis-antennary [C60]-fullerenes by double Passerini
and Ugi reactions; i) 27, TFA, CH2Cl2, r.t., 4 h; ii) 4-dimethylaminopyridine
(DMAP), tetrahydrofuran (THF), r.t., 24 h; iii) BBr3, CH2Cl2, r.t., 16 h; v) 28, tert-
butyl isocyanide, formaldehyde, aniline, CH2Cl2:MeOH (3:1), r.t., 48 h; iv) 28,
cyclohexyl isocyanide, isobutyraldehyde, CH2Cl2:MeOH (3:1), r.t., 48 h.
Currently, fullerenes and their derivatives have been studied
as photosensitizers mediating photodynamic therapy (PDT) in
various diseases.[6,19] The efficiency is related to the generation
of cytotoxic singlet oxygen (1O2), which causes oxidative stress
and membrane damage in the treated cells, leading to cell
death.[20] The ability of the MCR-decorated fullerenes to pro-
duce 1O2 was monitored by the chemical trapping method,
which measures the photo-bleaching of 1,3-diphenylisobenzo-
furan (DPBF) in toluene. For this, the compounds 3, 4, 5, 8, and
15 were chosen as representatives of the new fullerene series.
It is well known that DPBF acts as a singlet molecular
oxygen scavenger, which is generated by type II photo-pro-
cesses to produce 1,2-dibenzoylbenzene that does not absorb
visible light.[21] Figure 3 depicts the time-dependent decrease
in the DPBF absorbance at 415 nm during irradiation of the
fullerene adduct 3 with a 660 nm laser beam, which is inside
of the so-called “therapeutic window”.[22] The plot of ln(A0/A)
versus irradiation time gives a straight line (R2 =0.9998) pass-
Excited by these results, we analyzed the differences caused
by the presence of other substituents in the structure of com-
pounds 4, 5, 8, and 15.
The capacity of singlet oxygen production of these com-
pounds was also evaluated and the FD values are shown in
Table 1. As observed, there is a clear relation between the gen-
eration of singlet oxygen and the different moieties in the
structure of the fullerenes. With the tert-butyl group attached
to the chimeric fullereno-peptoid 3, a higher production of cy-
Table 1. Singlet oxygen quantum yield (FD) values for evaluated com-
pounds.
Compound
FD
Compound
FD
pristine C60
3
4
1.00[a]
0.91
5
8
15
0.47
0.37
0.69
0.64
[a] From reference [25].
totoxic 1O2 was observed, as compared with the cyclohexyl
group in 5. Furthermore, removal of the iso-propyl group in 4
1
also decreased the activity for the O2 generation as well as
the addition of a polar chain in adduct 8, that showed a nega-
tive effect in this ability. The modification of bisamide 3 to
depsipeptide 15 also contributed for decreasing the photoac-
tivity of this type of compounds.
Besides slight different solubilities of the compounds evalu-
ated, one of the main reasons for the variation in the photoac-
tivity may be attributed to the decreased aggregation compar-
ing peptoids 3–5. The attached peptoid-moieties tend to exist
in an equilibrium of cis/trans peptide bonds. The tert-butyl
moiety is known to lock peptoid bonds preferentially into a
Figure 3. Photooxidation of DPBF in the presence of 3 in toluene. Insert
figure shows the first order kinetics.
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1
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Keywords: diversification
multicomponent reactions · photodynamic therapy
·
fullerenes
·
isocyanides
·
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Manuscript received: May 14, 2018
Version of record online: && &&, 0000
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ÝÝ These are not the final page numbers!

Communication
COMMUNICATION
Supplying the MCR power plant: A
new protocol enables the diversity-
driven decoration of fullerenes via isocy-
anide-based multicomponent reactions
(Ugi-four component, U-4CR, and Pas-
serini-three component, P-3CR, reaction)
giving products with excellent yields
and a high atom economy. Evaluation
of highly diversified fullerenes as photo-
sensitizers showed promising results,
demonstrating possible applications in
photodynamic therapies.
&
Multicomponent Reactions
B. B. Ravanello, N. Seixas,
O. E. D. Rodrigues, R. S. da Silva,
M. A. Villetti, A. Frolov, D. G. Rivera,
B. Westermann*
&& – &&
Diversity Driven Decoration and
Ligation of Fullerene by Ugi and
Passerini Multicomponent Reactions
Chem. Eur. J. 2018, 24, 1 – 7
www.chemeurj.org
7
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ